Chemical synthesis provides the capacity to produce chemotherapeutic agents, and chemical reactions are the irreplaceable tools of the medicinal chemist engaged in the drug discovery process. Advances in chemical reaction methods reduce the interval between the conception of the chemical entity as a potential drug candidate and its synthesis for subsequent biological evaluation. As a consequence, organic synthesis is a critical discipline that continues to have an important impact on the fields of both medicine and biology. The objectives of this ongoing proposed research are to make creative contributions to the synthesis of complex naturally occuring substances possessing clinically significant biological activity. The targets for synthesis include manzamine A &ircinal A, nakadomarin A, spiro-prorocentrimine, himandridine, and cyclomarin A. Manzamine A was the first member in its family to be isolated from marine sponges found off the coast of Okinawa. The manzamines, including nakadomarin, represent a family of marine natural products that exhibit potent antitumor, antimalarial, and antituberculosis activity. Additionally, manzamine A selectively inhibits two main kinases implicated in the progression of Alzheimer's disease. As with many marine natural products, a lack of material for detailed biological screening is the motivation for the development of efficient routes to the synthesis of the individual members of this important family of natural products. Himandridine is one of the most complex members of the Galbulimima family of alkaloids. Historically, the native tribes of Papua New Guinea and Australia have used extracts of the bark of Galbulimima belgraveana for medicinal purposes. The attraction of both Himandridine and spiro-prorocentrimine to the organic chemist is their exceptional structural complexity. These targets are among the most complex alkaloids being addressed by total synthesis. The proposed syntheses of the indicated targets, in most instances, follow the speculated biosyntheses of the individual natural products. Multi-step reaction cascades have been designed into each of the synthesis plans. PUBLIC HEALTH RELEVANCE: Chemical synthesis enables the production chemotsherapeutic agents, and chemical reactions are the critical tools of the medicinal chemist engaged in drug discovery. Advances in reaction methodology reduce the interval between drug candidate conception and its synthesis for biological evaluation. Consequently, organic synthesis is a critical discipline that continues to have a pivotal impact on the fields of both medicine and biology. This grant will focus on the synthesis of bioactive alkaloids and peptides.